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microRNA-33 Regulates Macrophage Autophagy in Atherosclerosis.

Citation
Ouimet, Mireille, et al. “MicroRNA-33 Regulates Macrophage Autophagy in Atherosclerosis”. 2017. Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 37, no. 6, 2017, pp. 1058–1067.
Center Albert Einstein College of Medicine
Author Mireille Ouimet, Hasini Ediriweera, Milessa Silva Afonso, Bhama Ramkhelawon, Ragunath Singaravelu, Xianghai Liao, Rachel C Bandler, Karishma Rahman, Edward A Fisher, Katey J Rayner, John P Pezacki, Ira Tabas, Kathryn J Moore
Keywords atherosclerosis, Autophagy, hydrolysis, lipid droplets, macrophages
Abstract

OBJECTIVE: Defective autophagy in macrophages leads to pathological processes that contribute to atherosclerosis, including impaired cholesterol metabolism and defective efferocytosis. Autophagy promotes the degradation of cytoplasmic components in lysosomes and plays a key role in the catabolism of stored lipids to maintain cellular homeostasis. microRNA-33 (miR-33) is a post-transcriptional regulator of genes involved in cholesterol homeostasis, yet the complete mechanisms by which miR-33 controls lipid metabolism are unknown. We investigated whether miR-33 targeting of autophagy contributes to its regulation of cholesterol homeostasis and atherogenesis.

APPROACH AND RESULTS: Using coherent anti-Stokes Raman scattering microscopy, we show that miR-33 drives lipid droplet accumulation in macrophages, suggesting decreased lipolysis. Inhibition of neutral and lysosomal hydrolysis pathways revealed that miR-33 reduced cholesterol mobilization by a lysosomal-dependent mechanism, implicating repression of autophagy. Indeed, we show that miR-33 targets key autophagy regulators and effectors in macrophages to reduce lipid droplet catabolism, an essential process to generate free cholesterol for efflux. Notably, miR-33 regulation of autophagy lies upstream of its known effects on ABCA1 (ATP-binding cassette transporter A1)-dependent cholesterol efflux, as miR-33 inhibitors fail to increase efflux upon genetic or chemical inhibition of autophagy. Furthermore, we find that miR-33 inhibits apoptotic cell clearance via an autophagy-dependent mechanism. Macrophages treated with anti-miR-33 show increased efferocytosis, lysosomal biogenesis, and degradation of apoptotic material. Finally, we show that treating atherosclerotic mice with anti-miR-33 restores defective autophagy in macrophage foam cells and plaques and promotes apoptotic cell clearance to reduce plaque necrosis.

CONCLUSIONS: Collectively, these data provide insight into the mechanisms by which miR-33 regulates cellular cholesterol homeostasis and atherosclerosis.

Year of Publication
2017
Journal
Arteriosclerosis, thrombosis, and vascular biology
Volume
37
Issue
6
Number of Pages
1058-1067
Date Published
12/2017
ISSN Number
1524-4636
DOI
10.1161/ATVBAHA.116.308916
Alternate Journal
Arterioscler. Thromb. Vasc. Biol.
PMID
28428217
PMCID
PMC5494696
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